This is a new grant application to study the mechanisms by which chronic vigorous exercise suppresses reproductive function in a representative primate species, Macaca fascicularis. We have recently developed a monkey model in which female monkeys that exercise daily on treadmills develop reproductive dysfunction similar to that reported in human athletes. The overall goal of this grant proposal is to utilize this model in order to elucidate the physiological mechanisms by which chronic exercise leads to reproductive dysfunction. It is generally believed that exercise suppresses reproductive function at the level of hypothalamus by suppressing activity of GnRH-containing neurons. If this is true, then use of the exercising monkey model will allow us to explore the basic mechanisms by which GnRH neuronal activity can be suppressed (a phenomenon seen in the physiological and pathological conditions of normal childhood, severe undernutrition, anorexia nervosa, spontaneous hypothalamic-hypophyseal dysfunction, and stress, as well as during participation in chronic vigorous exercise programs). The first specific aim of this grant is to test the hypothesis that changes in menstrual cyclicity and ovarian function that occur during vigorous exercise training causes reproductive dysfunction by determining whether the hypothalamic-pituitary-adrenal axis and/or the opioid-secreting neurons of the central nervous system are activated during vigorous exercise training. Further experiments will test whether blocking these systems by using antagonists to CRF (i.e., alpha-helical CRF) or beta-endorphin (i.e., naloxone) will restore normal reproductive function. The third aim of this grant is to test the hypothesis that metabolic changes occurring in response to the increased energy utilization of vigorous exercise cause exercise-induced reproductive dysfunction. If this is successful, we will identify metabolic changes and central neurotransmitter changes that may serve as key signals to modulate reproductive function in times of low energy balance. In summary, the experiments in this grant proposal will greatly increase our understanding of the mechanisms by which internal and external influences can modify the activity of the hypothalamic-pituitary-ovarian axis.